Novel N-(substituted-phenyl)-5-(substituted-2,5-dimethylphenoxy)-2,2-dimethylpentanamides

ABSTRACT

Novel N-(substituted-phenyl)-5-(substituted-2,5-dimethylphenoxy)-2,2- dimethylpentanamides which are useful in preventing the intestinal absorption of cholesterol and also increasing high-density lipoprotein (HDL) cholesterol, as well as novel pharmaceutical compositions and methods of use, as well as processes for their manufacture are herein described.

CROSS REFERENCE TO RELATED APPLICATION

This application is a division of Applicants' copending application,U.S. Ser. No. 219,964 filed July 15, 1988, which application issued Nov.21, 1989 as U.S. Pat. No. 4,882,357.

BACKGROUND OF THE INVENTION

The present invention relates to novel substituted amides useful aspharmaceutical agents, to methods for their production, topharmaceutical compositions which include these compounds and apharmaceutically acceptable carrier, and to a pharmaceutical method oftreatment. More particularly, the novel compounds of the presentinvention lower low density lipoprotein cholesterol (LDL) and elevatehigh density lipoprotein cholesterol (HDL). Both of these effects affordprotection from coronary heart disease.

The atheromatous plaque, which is the characteristic lesion ofatherosclerosis, results from deposition of plasma lipids, mainlycholesteryl esters, in the intima of the arterial wall. Progressiveenlargement of the plaque leads to arterial constriction and ultimatelycoronary heart disease. Two recent clinical trials have shown a causalrelationship between serum levels of LDL- and HDL-cholesterol andcoronary heart disease.

In 1984, the Lipid Research Clinics-Coronary Prevention Trial (LRC-CPPT)demonstrated for the first time that lowering LDL cholesterol wouldreduce coronary heart disease. Very recently the results of a five-year,4,081-patient clinical trial published in the New England Journal ofMedicine, 317, pp 1237-1245 (1987) demonstrated that the lipidregulating drug, gemfibrozil, reduced the rate of heart attack andsudden cardiac death by 34 percent in patients with elevated cholesterollevels. Gemfibrozil both lowers LDL and elevates HDL; but if the resultsfrom the LRC-CPPT study are utilized to estimate the expected reductionin incidence of heart attack and heart disease due to lowering of LDL,it amounts to approximately one-half of the effect actually observed.Thus, there appears to be little doubt as to the benefit of elevatingHDL.

The compounds of this invention combine two mechanisms of action toachieve their improved activity in lowering LDL and elevating HDL. Notonly do they show the same effects as gemfibrozil but, in addition, theyinhibit the enzyme acyl-CoA:cholesterol acyltransferase (ACAT).

Dietary cholesterol is absorbed from the intestinal lumen as freecholesterol which must be esterified with fatty acids. This reaction iscatalyzed by ACAT. The resulting cholesteryl esters are packaged intothe chylomicrons which are secreted into the lymph. Inhibitors of ACATnot only prevent absorption of dietary cholesterol but also prevent thereabsorption of cholesterol which has been released into the intestinethrough endogenous regulatory mechanisms, thus lowering LDL cholesterollevels and ultimately preventing the further development ofatherosclerosis.

Prior work on amides of gemfibrozil (U.S. Pat. No. 4,413,011 to Sircar,I and Holmes, A, issued Nov. 1, 1983) identified those compounds thatretained the original lipid modulating activity of the parent drug whichis demonstrated by the elevation of HDL in rats. The present compoundsdiffer in that they have been chosen for their superior inhibition ofACAT, and thus they possess two different mechanisms of action thatcomplement each other. Thus, gemfibrozil speeds up the metabolism of LDLin the liver, and the excess cholesterol is released into the intestinesvia the bile. Normally a portion of this cholesterol is reabsorbed andultimately recirculated in the form of new LDL. However, this isprevented in the presence of an ACAT inhibitor.

SUMMARY OF THE INVENTION

Accordingly, a first aspect of the present invention is a compound ofFormula I ##STR1## or a pharmaceutically acceptable acid addition saltthereof, wherein A is hydrogen, hydroxy, alkoxy of from one to sixcarbon atoms or ##STR2## in which R is an alkyl group of from one to sixcarbon atoms; X and Y are each independently hydrogen, fluorine, nitro,--NH₂, --NHR, in which R is as defined above, --NRR, in which R is asdefined above, alkyl of from one to six carbon atoms, alkoxy of from oneto six carbon atoms which may be substituted at the terminal carbon atomby --CO₂ R, in which R is as defined above; Z and W are eachindependently hydrogen, fluorine, alkyl of from one to six carbon atomsor alkoxy of from one to six carbon atoms, which may be substituted atthe terminal carbon atom by --CO₂ R, in which R is as defined above, andat least one of X, Y, Z or W is not hydrogen; or wherein one of X, Y, Zor W together with its vicinal member forms a methylenedioxy group.

Additionally, the present invention is directed to a pharmaceuticalcomposition useful for inhibiting intestinal absorption of cholesteroland also for increasing high-density lipoprotein (HDL) cholesterol inmammals comprising an effective amount of a compound of Formula I asdefined above with a pharmaceutically acceptable carrier.

Also, the present invention is directed to a novel method of inhibitingintestinal absorption of cholesterol and also increasing high-densitylipoprotein (HDL) cholesterol in mammals comprising administering aneffective amount of a compound of Formula I as defined above.

Finally, the present invention is directed to methods for production ofa compound of Formula I as defined above.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of Formula I, the term "alkyl" means a straight orbranched hydrocarbon group having from one to eight carbon atoms andincludes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tertiary-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and thelike.

"Alkoxy" is O-alkyl in which alkyl is as defined above.

"Halogen" is iodine, bromine, chlorine, and fluorine.

A preferred group of compounds are those of Formula II ##STR3## whereinX, Y, Z, and W are as defined above.

A most preferred group of compounds are those of Formula II wherein X ishydrogen, fluorine, alkyl of from one to six carbon atoms, or alkoxy offrom one to six carbon atoms which may be substituted at the terminalcarbon atom by --CO₂ R in which R is as defined above; Y is hydrogen,nitro, --NH₂, --NHR, in which R is as defined above, --NRR, in which Ris as defined above, alkyl of from one to six carbon atoms, or alkoxy offrom one to six carbon atoms which may be substituted at the terminalcarbon atom by --CO₂ R, in which R is as defined above; Z is hydrogen,fluorine, alkyl of from one to six carbon atoms, alkoxy of from one tosix carbon atoms which may be substituted at the terminal carbon atom by--CO₂ R, in which R is as defined above, or Y and Z taken together forma methylenedioxy group; and W is hydrogen, fluorine, alkyl of from oneto six carbon atoms, alkoxy of from one to six carbon atoms which may besubstituted at the terminal carbon atom by --CO₂ R, in which R is asdefined above.

Particularly valuable are:

5-(2,5-Dimethylphenoxy)-N-(2-methoxyphenyl)-2,2-dimethylpentanamide;

5-(2,5-Dimethylphenoxy)-N-(2-methoxy-4-methylphenyl)-2,2-dimethylpentanamide;

5-(2,5-Dimethylphenoxy)-N-(2,4-dimethylphenyl)-2,2-dimethylpentanamide;

N-(3,4-Dimethoxyphenyl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide;

5-(2,5-Dimethylphenoxy)-N-(2-ethoxyphenyl)-2,2-dimethylpentanamide;

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-[2-(1-methylethoxy)phenyl]-pentanamide;

5-(2,5-Dimethylphenoxy)-N-[2-(hexyloxy)phenyl]-2,2-dimethylpentanamide;

N-(2,4-Difluorophenyl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide;

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(2,4,6-trifluorophenyl)pentanamide;

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(3-nitrophenyl)pentanamide;

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-[4-methyl-2(1-methylethoxy)phenyl]pentanamide;

N-1,3-Benzodioxol-5-yl-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide;

5-[3-[[5-(2,5-Dimethylphenoxy)-2,2-dimethyl-1-oxopentyl]amino]phenoxy]-2,2-dimethylpentanoicacid, methyl ester;

5-[2-[[5-(2,5-Dimethylphenoxy)-2,2-dimethyl-1-oxopentyl]amino]phenoxy-2,2-dimethylpentanoicacid, methyl ester;

5-[4-[[5-(2,5-Dimethylphenoxy)-2,2-dimethyl-1-oxopentyl]amino]-2,5-dimethylphenoxy]-2,2-dimethylpentanoicacid, methyl ester;

N-(3-Aminophenyl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide;

5-[4-[[5-(2,5-dimethylphenoxy)-2,2-dimethyl-1-oxopentyl]amino]phenoxy]-2,2-dimethylpentanoicacid, methyl ester; or a pharmaceutically acceptable acid addition saltthereof.

The process of preparing compounds of the present invention is describedgenerally as follows:

A compound having the Formula I ##STR4## or a pharmaceuticallyacceptable acid addition salt thereof, wherein A is hydrogen, hydroxy,alkoxy of from one to six carbon atoms or ##STR5## in which R is analkyl group of from one to six carbon atoms; X and Y are eachindependently hydrogen, fluorine, nitro, --NH₂, NHR, in which R is asdefined above, --NRR, in which R is as defined above, alkyl of from oneto six carbon atoms, alkoxy from one to six carbon atoms which may besubstituted at the terminal carbon atom by --CO₂ R, in which R is asdefined above; Z and W are each independently hydrogen, fluorine, alkylof from one to six carbon atoms or alkoxy of from one to six carbonatoms, which may be substituted at the terminal carbon atom by --CO₂ R,in which R is as defined above, and at least one of X, Y, Z or W is nothydrogen; or wherein one of X, Y, Z or W taken together with its vicinalmember forms a methylenedioxy group; is prepared by coupling a compoundof Formula III ##STR6## wherein X, Y, Z, and W are as described abovewith a compound of Formula IV ##STR7## wherein R₂ is a leaving group andA is as described above.

Preferred coupling methods involve contacting a compound of Formula IIIwith acylhalides of the Formula V ##STR8## wherein Hal is halogen,preferably chlorine or bromine and A is as described above.

The reaction is carried out in nonaqueous solvent such as acetonitrile,tetrahydrofuran or methylene chloride, preferably methylene chloride,with an added organic base such as triethylamine or pyridine, preferablytriethylamine, if needed at temperatures between -10° C. and the refluxtemperature of the solvent, preferably at 0° C.

Compounds of Formula III are either known or capable of being preparedby methods known in the art.

Compounds of Formula IV are obtained by appropriately activating acompound of Formula VI ##STR9## wherein A is as described above with acarboxyl activating group such as described in E. Schroeder and K.Lubke, "The Peptides," Vol. 1, Chapt. III, Academic Press, 1966.

Compounds of Formula VI are either known or capable of being prepared bymethods known in the art.

A compound of Formula I also may be prepared by contacting a compound ofFormula VII ##STR10## wherein A is as described above with a compound ofFormula VIII ##STR11## wherein Hal, X, Y, Z, and W are as defined above.

The reaction is carried out in the presence of a base such as, forexample, sodium hydroxide, potassium carbonate, and the like innonaqueous solvent such as, for example, tetrahydrofuran at temperaturesbetween 0° C. and the reflux temperature of the solvent, preferably atthe reflux temperature of the solvent.

Compounds of Formula VII are either known or capable of being preparedby methods known in the art.

Compounds of Formula VIII are obtained by contacting a compound ofFormula IX ##STR12## wherein Hal is as described above with a compoundof Formula III.

The reaction is carried out in nonaqueous solvent such as acetonitrile,tetrahydrofuran or methylene chloride, preferably methylene chloride,with an added organic base such as triethylamine or pyridine, preferablytriethylamine, if needed at temperatures between -10° C. and the refluxtemperature of the solvent, preferably at 0° C.

Compounds of Formula IX are either known or capable of being prepared bymethods known in the art.

The products of the reactions described herein are isolated byconventional means such as chromatography, recrystallization,distillation, and the like. Generally, the starting materials are known,commercially available, or synthesized by known methods.

The compounds of the present invention were tested for their ability toinhibit the esterification of cholesterol by the enzymeacyl-CoA:cholesterol acyltransferase (ACAT). The data in the table belowis expressed as IC₅₀ values, i.e., the concentration of test compoundrequired to inhibit cholesteryl oleate formation to 50% of control. Thedata in the table shows the ability of representative compounds of thepresent invention to potently inhibit ACAT.

The in vitro test employed is more fully described in Field, F. J. andSalome, R. G., Biochemica et Biophysica Acta, 712, pp 557-570 (1982).The assay evaluates the ability of a test compound to inhibit theesterification of cholesterol using endogenous cholesterol of a rabbitintestinal microsomal fraction and exogenous ¹⁴ C-oleoyl-CoA asreactants.

Additionally, the elevation of HDL is reported in the table as a ratioof the elevation of HDL effected by a dose of 50 mg/kg of the test drugdivided by the elevation of HDL effected by a 50 mg/kg dose ofgemfibrozil which is used as a control in each experiment. ##EQU1##Thus, a figure of 1 means that the test drug was as effective asgemfibrozil in elevating HDL. Values greater than 1 suggest that thetest drug is more effective than gemfibrozil. The test procedure isdescribed in U.S. Pat. No. 4,413,011.

                                      TABLE                                       __________________________________________________________________________    Biological Activity of Compounds of Formula I                                 Example Number                                                                        Compound               IC.sub.50 (μmoles)                                                               ##STR13##                                __________________________________________________________________________    1a     5-(2,5-Dimethylphenoxy)- .sub.--N-(2-methoxy-4-methyl-                                                6    0.80                                             phenyl)-2,2-dimethylpentanamide                                        1b     5-(2,5-Dimethylphenoxy)- .sub.--N-(2,4-dimethylphenyl)-                                               8    1.29                                             2,2-dimethylpentanamide                                                1d     5-(2,5-Dimethylphenoxy)- .sub.--N-(2-ethoxyphenyl)-2,2-                                               5    1.08                                             dimethylpentanamide                                                    1c      .sub.--N-(3,4-Dimethoxyphenyl)-5-(2,5-dimethylphenoxy)-                                              3    1.10                                             2,2-dimethylpentanamide                                                1j     5-(2,5-Dimethylphenoxy)-2,2-dimethyl- .sub.--N[4-methyl-                                              8    0.84                                             2-(1-methylethoxy)phenyl]-pentanamide                                  1g      .sub.--N-(2,4-Difluorophenyl)-5-(2,5-dimethylphenoxy)-                                               7    0.36                                             2,2-dimethylpentanamide                                                1h     5-(2,5-Dimethylphenoxy)-2,2-dimethyl- .sub.--N-(2,4,6-                                                0.8  0.74                                             trifluorophenyl)-pentanamide                                           1k      .sub.--N-1,3-Benzodioxol-5-yl-5-(2,5-dimethyl-                                                       6    1.13                                             phenoxy)-2,2-dimethylpentanamide                                       1m     5-[3-[[5-(2,5-Dimethylphenoxy)-2,2-dimethyl-1-                                                        21   1.0                                              oxopentyl]amino]phenoxy]-2,2-dimethylpentanoic                                acid, methyl ester                                                     1l     5-[2-[[5-(2,5-Dimethylphenoxy)-2,2-dimethyl-1-                                                        8    0.4                                              oxopentyl]amino]phenoxy-2,2-dimethylpentanoic                                 acid, methyl ester                                                     1      5-(2,5-Dimethylphenoxy)- .sub.--N-(2-methoxyphenyl)-                                                  14   0.31                                             2,2-dimethylpentanamide                                                1f     5-(2,5-Dimethylphenoxy)- .sub.--N-[2-(hexyloxy)phenyl]-                                               10   0.42                                             2,2-dimethylpentanamide                                                Example 5                                                                            3-[4-[[5-(2,5-Dimethylphenoxy)-2,2-dimethyl-1-                                                        45   0.56                                      U.S.   oxopentyl]amino]pentyl]-2-propenoic acid, ethyl                        Pat. No.                                                                             ester                                                                  4,413,011)                                                                    __________________________________________________________________________

Therefore, the compounds of the present invention are useful inpharmaceutical formulations for preventing absorption of dietarycholesterol or the reabsorption of cholesterol which has been releasedinto the intestines through endogenous regulatory mechanisms and alsofor increasing HDL cholesterol levels.

The present invention also includes a method for treatinghypercholesterolemia comprising administering to mammals, includinghumans, the corresponding pharmaceutical composition. The compositioncontains a compound of Formula I as defined before in an appropriateunit dosage form.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, and dispersible granules. A solid carrier can be one ormore substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active compound is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term "preparation" is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component, with or without other carriers,is surrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted shortly before use to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet orlozenge itself or it can be the appropriate number of any of these inpackaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 50 mg to 500 mg, preferably 100 mg to 300 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

The dosage range for a 70-kg mammal is from 1 mg/kg to 100 mg/kg of bodyweight per day or preferably 3 mg/kg to 15 mg/kg of body weight per daywhen the compounds of the present invention are used therapeutically toinhibit the intestinal absorption of cholesterol and also increase HDLcholesterol levels. However, dosages may be varied depending upon thecompound used, the severity of the condition being treated, and therequirements of the patient. Determination of the appropriate dosage fora particular situation is within the skill of the art.

The invention is further illustrated but not limited by the followingexamples.

EXAMPLE 15-(2,5-Dimethylphenoxy)-N-(2-methoxyphenyl)-2,2-dimethylpentanamide

To a solution of 3.7 g (0.03 mol) of 2-methoxybenzenamine and 3.03 g(0.03 mol) of triethylamine in 100 ml of tetrahydrofuran is addeddropwise with stirring 7.7 g (0.03 mol) of5-(2,5-dimethylphenoxy)-2,2-dimethylpentamoyl chloride (U.S. Pat. No.4,285,951). The mixture is stirred at room temperature overnight,filtered, and the filtrate concentrated in vacuo. Water is added to theresidue and the solid filtered to afford 7.9 g of5-(2,5-dimethylphenoxy)-N-(2-methoxyphenyl)-2,2-dimethylpentanamide as awhite solid after recrystallization from pentane; mp 47°-48° C.

EXAMPLE 1a5-(2,5-Dimethylphenoxy)-N-(2-methoxy-4-methylphenyl)-2,2-dimethylpentanamid

In a process analogous to Example 1 by substituting2-methoxy-4-methylbenzenamine (Journal of Medicinal Chemistry, Vol. 22,pp 63-69 (1979), for 2-methoxybenzenamine one obtains5-(2,5-dimethylphenoxy)-N-(2-methoxy-4-methylphenyl)-2,2-dimethylpentanamide;bp 190°-195° C. (0.50 mm).

EXAMPLE 1b5-(2,5-Dimethylphenoxy)-N-(2,4-dimethylphenyl)-2,2-dimethylpentanamide

In a process analogous to Example 1 by substituting2,4-dimethylbenzenamine for 2-methoxybenzenamine one obtains5-(2,5-dimethylphenoxy)-N-(2,4-dimethylphenyl)-2,2-dimethylpentanamide;mp 80°-82° C.

EXAMPLE 1cN-(3,4-Dimethoxyphenyl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide

In a process analogous to Example 1 by substituting3,4-dimethoxybenzenamine for 2-methoxybenzenamine one obtainsN-(3,4-dimethoxyphenyl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide;mp 110°-111° C.

EXAMPLE 1d5-(2,5-Dimethylphenoxy)-N-(2-ethoxyphenyl)-2,2-dimethylpentanamide

In a process analogous to Example 1 by substituting 2-ethoxybenzenaminefor 2-methoxybenzenamine one obtains5-(2,5-dimethylphenoxy)-N-(2-ethoxyphenyl)-2,2-dimethylpentanamide; mp59°-60° C.

EXAMPLE 1e5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N[2-(1-methylethoxy)phenyl]pentanamide

In a process analogous to Example 1 by substituting2-(1-methylethoxy)benzenamine (Example A) for 2-methoxybenzenamine oneobtains5-(2,5-dimethylphenoxy)-2,2-dimethyl-N[2-(1-methylethoxy)phenyl]pentanamideas a viscous liquid.

EXAMPLE 1f5-(2,5-Dimethylphenoxy)-N[2-(hexyloxy)phenyl]-2,2-dimethylpentanamide

In a process analogous to Example 1 by substituting2-(hexyloxy)benzenamine (Example B) for 2-methoxybenzenamine one obtains5-(2,5-dimethylphenoxy)-N[2-(hexyloxy)phenyl]-2,2-dimethylpentanamide asa viscous liquid.

EXAMPLE 1gN-(2,4-Difluorophenyl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide

In a process analogous to Example 1 by substituting2,4-difluorobenzenamine for 2-methoxybenzenamine one obtainsN-(2,4-difluorophenyl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide;mp 79°-80° C.

EXAMPLE 1h5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(2,4,6-trifluorophenyl)pentanamide

In a process analogous to Example 1 by substituting2,4,6-trifluorobenzenamine for 2-methoxybenzenamine one obtains5-(2,5-dimethylphenoxy)-2,2-dimethyl-N-(2,4,6-trifluorophenyl)pentanamide;mp 82°-83° C.

EXAMPLE 1i5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(3-nitrophenyl)pentanamide

In a process analogous to Example 1 by substituting 3-nitrobenzenaminefor 2-methoxybenzenamine one obtains5-(2,5-dimethylphenoxy)2,2-dimethyl-N-(3-nitrophenyl)pentanamide; mp93°-94° C.

EXAMPLE 1j5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-[4-methyl-2-(1-methylethoxy)phenyl]pentanamide

In a process analogous to Example 1 by substituting4-methyl-2-(1-methylethoxy)benzenamine (Example C) for2-methoxybenzenamine one obtains5-(2,5-dimethylphenoxy)-2,2-dimethyl-N-[4-methyl-2-(1-methylethoxy)phenyl]pentanamideas a viscous liquid; bp 193°-197° C. (0.50 mm).

EXAMPLE 1kN-1,3-Benzodioxol-5-yl-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide

In a process analogous to Example 1 by substituting1,3-benzodioxol-5-amine for 2-methoxybenzenamine one obtainsN-1,3-benzodioxol-5-yl-5(2,5-dimethylphenoxy)-2,2-dimethylpentanamide;mp 89°-90° C.

EXAMPLE 1l5-(2-[[5-(2,5-Dimethylphenoxy)-2,2-dimethyl-1-oxopentyl]amino]phenoxy]-2,2-dimethylpentanoicacid, methyl ester

In a process analogous to Example 1 by substituting5-(2-aminophenoxy)-2,2-dimethylpentanoic acid, methyl ester (Example D)for 2-methoxybenzenamine one obtains5-[2[[5-(2,5-dimethylphenoxy)-2,2-dimethyl-1-oxopentyl]amino]phenoxy]-2,2-dimethylpentanoicacid, methyl ester as an oil; 1R 1732, 1685 cm⁻¹.

EXAMPLE 1m5-[3-[[5-(2,5-Dimethylphenoxy)-2,2-dimethyl-1-oxopentyl]amino]phenoxy]-2,2-dimethylpentanoicacid, methyl ester

In a process analogous to Example 1 by substituting5-(3-aminophenoxy)-2,2-dimethylpentanoic acid, methyl ester (Example E)for 2-methoxybenzenamine one obtains5-[3-[[5-(2,5-dimethylphenoxy)-2,2-dimethyl-1-oxopentyl]amino]phenoxy]-2,2-dimethylpentanoicacid, methyl ester; 1R 1732, 1661 cm⁻¹.

EXAMPLE 1n5-[4-[[5-(2,5-Dimethylphenoxy)-2,2-dimethyl-1-oxopentyl]amino]-2,5-dimethylphenoxy]-2,2-dimethylpentanoicacid, methyl ester

In a process analogous to Example 1 by substituting5-[4-amino-2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, methyl ester(Example F) for 2-methoxybenzenamine one obtains5-[4-[[5-(2,5-dimethylphenoxy)-2,2-dimethyl-1-oxopentyl]amino]-2,5-dimethylphenoxy]-2,2-dimethylpentanoicacid, methyl ester; mp 60°-62° C.

EXAMPLE 25-[4-[[5-(2,5-Dimethylphenoxy)-2,2-dimethyl-1-oxopentyl]amino]phenoxy]-2,2-dimethylpentanoicacid, methyl ester

In a process analogous to Example 1 by substituting 4-aminophenol for2-methoxybenzenamine one obtains5-(2,5-dimethylphenoxy)-N-(4-hydroxyphenyl)-2,2-dimethylpentanamide asan oil.

Sodium hydride, 50% dispersion in mineral oil, 2.2 g, is added to 15.3 gof 5-(2,5-dimethylphenoxy)-N-(4-hydroxyphenyl)-2,2-dimethylpentanamidein 200 ml of N,N-dimethylformamide (DMF). Then 10 g of methyl5-bromo-2,2-dimethylpentanoate (Journal of Medicinal Chemistry, Vol. 26,pp 1020-1027 (1983)) is added to the previous mixture. The mixture isstirred overnight and then stirred three hours on a steam bath, the DMFis removed on a rotary evaporator and water is added to the residue. Theproduct is taken up in diethyl ether, extracted with base, washed withwater and concentrated on a steam bath. Isopropyl ether is added toafford 10.4 g of5-[4-[[5-(2,5-dimethylphenoxy)-2,2-dimethyl-1-oxopentyl]amino]phenoxy]-2,2-dimethylpentanoicacid, methyl ester after recrystallization from isopropyl ether (2X); mp62°-63° C.

EXAMPLE 3N-(3-Aminophenyl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide

5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(3-nitrophenyl)pentanamide(Example 1i), 22.39 g (0.0604 mol), is dissolved in 400 ml of methanol,1.5 g of Raney nickel is added and the mixture is exposed to hydrogengas until the required amount of hydrogen is absorbed. The methanolsolution is filtered and concentrated in vacuo and the residue solidifesto afford 19.8 g ofN-(3-aminophenyl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide afterrecrystallization from isopropyl ether; mp 93°-94° C.

PREPARATIVE EXAMPLES FOR INTERMEDIATES EXAMPLE A2-(1-Methylethoxy)benzenamine

2-Nitrophenol sodium salt, 64.4 g (0.4 mol), and 67.99 g (0.4 mol) of2-iodopropane are combined in 400 ml N,N-dimethylformamide and stirredand refluxed overnight. The resulting mixture is cooled, concentrated invacuo, and the residue taken up in water and the oil extracted intodiethyl ether. The diethyl ether layer is separated, washed with 500 mlof 10% sodium hydroxide, water (2X), dried (magnesium sulfate),concentrated in vacuo to give after distillation 45.2 g (62.4%) of1-(1-methylethoxy)-2-nitrobenzene, bp 99°-101° C. at 0.1 mm.

1-(1-methylethoxy)-2-nitrobenzene, 45.26 g (0.25 mol) is dissolved in500 ml of methanol, 4 g Raney nickel is added and the mixture is exposedto hydrogen gas until the required amount of hydrogen is absorbed. Themethanol solution is filtered and concentrated in vacuo and the residuedistilled to give 35.7 g (94.4%) of 2-(1-methylethoxy)benzenamine; bp100-102 (at 4 mm).

EXAMPLE B 2-(Hexyloxy)benzenamine

2-Nitrophenol, sodium salt, 48.33 g (0.3 mol), and 1-bromohexane, 49.5 g(0.3 mol) in 300 ml of N,N-dimethylformamide are stirred and refluxedovernight. The resulting mixture is cooled, filtered, concentrated invacuo, water is added to the residue, and the oil is extracted intodiethyl ether. The diethyl ether layer is separated, washed with 5%sodium hydroxide, brine (2X), dried (magnesium sulfate), concentrated invacuo to give after distillation 61.9 g of 1-(hexyloxy)-2-nitrobenzene;bp 121°-124° C. at 0.075 mm.

1-(Hexyloxy)-2-nitrobenzene, 61.28 g (0.27 mol) is dissolved in 700 mlof methanol, 3 g Raney nickel is added and the mixture exposed tohydrogen gas until the required amount of hydrogen is absorbed. Themethanol solution is filtered and concentrated in vacuo and the residuedistilled to give 50 g of 2-(hexyloxy)benzenamine; bp 145°-148° C. at 4mm.

EXAMPLE C 4-Methyl-2-(1-methylethoxy)benzenamine

A mixture of 23 g (150 mmol) of 5-methyl-2-nitrophenol 28.1 g (1.1×150mmol) of 2-iodopropane and 22.8 g (1.1×150 mmol) of anhydrous potassiumcarbonate in 150 ml of acetonitrile is stirred and refluxed for 18 hoursovernight. The solids were removed, the solvent evaporated and theresidue is taken up in diethyl ether and the solution washed with 50 mlof 2N potassium hydroxide (2X), brine, dried (magnesium sulfate), andevaporated to an oil. Distillation gives 18.6 g (64%) of5-methyl-1-(1-methylethoxy)-2-nitrobenzene; bp 98°-100° C. at 0.5 mm.

5-Methyl-1-(1-methylethoxy)-2-nitrobenzene, 17.7 g (91 mmol), isdissolved in methanol, palladium on charcoal is added and the mixture isexposed to hydrogen gas until the required amount of hydrogen isabsorbed. The mixture is worked up in the usual manner to give 15 g of4-methyl-2-(1-methylethoxy)benzenamine.

EXAMPLE D 5-(2-aminophenoxy)-2,2-dimethylpentanoic acid, methyl ester

A mixture of 27.8 g (200 mmol) of 2-nitrophenol, 44.6 g (200 mmol) ofmethyl-5-bromo-2,2-dimethylpentanoate (Journal of Medicinal Chemistry,Vol. 26, pp 1020-1027 (1983)) and 30.5 g (220 mmol) of anhydrouspotassium carbonate in 300 ml of acetonitrile is stirred at reflux for18 hours. The inorganic salts are removed, washed with acetonitrile andthe filtrate is concentrated on a rotary evaporator. The residue istaken up in diethyl ether and the solution washed with 2N potassiumhydroxide (3×50 ml), brine, dried (magnesium sulfate), and evaporated toafford 55.9 g of crude product. Distillation gives 52.9 g of2,2-dimethyl-5-(3-nitrophenoxy)pentanoic acid, methyl ester, bp160°-165° C. (0.5 mm).

A solution of 5.6 g (20 mmol) of2,2-dimethyl-5-(3-nitrophenoxy)pentanoic acid, methyl ester, 0.5 g of 5%palladium on charcoal in 100 ml of methanol is shaken under threeatmospheres of hydrogen gas until the hydrogen uptake is complete. Thecatalyst is removed and the solvent evaporated. The residual oil istaken up in toluene and evaporated to remove traces of methanol toafford 5-(2-aminophenoxy)-2,2-dimethylpentanoic acid, methyl ester.

EXAMPLE E 5-(3-Aminophenoxy)-2,2-dimethylpentanoic acid, methyl ester

In a process analogous to Example D by substituting 3-nitrophenol for2-nitrophenol one obtains 5-(3-aminophenoxy)-2,2-dimethylpentanoic acid,methyl ester as an oil.

EXAMPLE F 5-[4-Amino-2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid,methyl ester

In a process analogous to Example D by substituting2,5-dimethyl-4-nitrophenol for 2-nitrophenol one obtains5-[4-amino-2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, methylester, monohydrochloride; mp 164°-166° C.

We claim:
 1. A compound of Formula I ##STR14## or a pharmaceuticallyacceptable acid addition salt thereof, where A is hydrogen, hydroxy,alkoxy of from one to six carbon atoms or ##STR15## in which R is analkyl group of from one to six carbon atoms; and one of X, Y, Z or Wtogether with its vicinal member forms a methylenedioxy group and theremaining X, Y, Z or W represent hydrogen.
 2. A compound as defined inclaim 1 having the Formula II ##STR16##
 3. A compound as defined inclaim 2 having the nameN-1,3-benzodioxol-5-yl-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide.4. A pharmaceutical composition useful for inhibiting the intestinalabsorption of cholesterol and also for increasing high-densitylipoprotein (HDL) cholesterol comprising an effective amount of acompound as defined by claim 1 in combination with a pharmaceuticallyacceptable carrier.
 5. A method of inhibiting intestinal absorption ofcholesterol and also increasing high-density lipoprotein (HDL)cholesterol in mammals comprising administering to said mammal aneffective amount of a compound as defined by claim 1 in combination witha pharmaceutically acceptable carrier.